2-arylmethylene-4a-methyl-6-hydroxy-1, 2, 3, 4, 4a, 9, 10, 10a-octahydro-1-phenanthrones and derivatives thereof



United States Patiitb i-ARYIMETHYLENE 4a METHYL-6 HYDROXY- 1,2,3,4,4a,9,10,10a OCTAHYDRO 1 PHENAN- THRONES AND DERIVATIVES THEREOF Willard M. Hoehn, Wilmette, and Roy H. Bible, In, Morton Grove, Ill., assignors to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Application January 24, 1957 Serial No. 635331 7 Claims. (Cl. 260-586) The present invention relates to methyl 6 -hydroxy phenanthrones and derivatives thereof. The compounds which constitute our invention can be represented by the general structural formula 2-arylmethylene-4a- OR C i In this formula, R can represent hydrogen or a hydrometal hydroxide or an alkali metal alkoxide, with an aromatic aldehyde of the formula wherein Ar is an aromatic hydrocarbon radical having fewer than 11 carbon atoms, or a halogenated derivative ereof. This reaction can be carried out at or below room temperature for a period of several days. It can also be carried out by briefly heating the mixture to about 90l00 0., followed by allowing'it to stand at room temperature fora period of up to several days. The

- 1,2,3,4,4-a,9,10,10 octahydro 1- sent the phenyl radical, an alkylated phenyl radical, a

naphthyl radical, or a monohalogen or polyhalogen substitution product of one of the foregoing.

This is a continuation-in-part of our copending application, Serial No. 338,151, filed February 20, 1953, now abandoned.

Suitable starting materials for the manufacture of the compositions of the present invention are alkyl and.

aralkyl ethers of 4a methyl 6 hydroxy 1,2,3,4,4a,9, 10,10a octahydro 1 phenanthrone described in U. S. 2,764,616. Another suitable yl 6 hydroxy l,2,3,4,4a,9,10,l0a octahydro l 7 phenanthrone, the phenol corresponding to the foregoing alkyl and aralkyl ethers, which is prepared by heating 4amethyl 6 methoxy 1,2,3,4,4a,9,l0,10a octahydrol-phenanthrone with pyridine hydrochloride. Such starting materials have the structural formula OR- a I l wherein R is defined as before.

In accordance with the methods described more fully in the examples to follow, such compounds are treated, suitably in alcoholic or aqueous alcoholic solution in the presence of a basic condensing agent such as an alkali starting material is 4a-meth- 1 They are also valuablemedicinal reaction product can thereupon be isolated by direct filtration in those 'instanceswhere it is insoluble In'those instances where" it is -phenolic and relatively soluble, it can be isolated bypartitioning the acidified mixture between ether and water; non-phenolic, relatively soluble reaction products can be isolated by partitioning the mixture between ether and-water without prior acidification. The recovery of the reaction product from the ethereal solution is completed by washing with a base such as dilute sodium bicarbonate, and vaporizing the solvents. Manyof the compositions of this invention are highboiling, viscous oils or glasses whichcan be conveniently purified by distillation in a short-path 'distillation apparatus.

The compositions of this invention are useful in the prevention of actinic dermatitis. For example, upon topical applicatiomfisuitably in corn oil solution, they inhibit the development of: sunburn and other erythemal effects caused by excessive exposure to ultraviolet radiation. and especially hormonal agents useful in the correction of metabolic dysfunction. One of the means which can be employed for demonstrating their effect on tissue metabolism is the Warburg respirometer. A particular pharmacological utility of the compounds of this invention is their effectiveness as antidiuretic agents. I a

This invention will appear more fully from the examples w ch follow. These examples are set forth by way 'of illustration only, and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials 'andmethods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.), distillation pressures inmillimeters (mm.) of mercury, and quantities of materials in parts by weight.

:EXAMPLEyl v Ether: of 4a-methyl-6-hydroxy-1,2,3,4,4a,9,10,10aoctahydro-I-phenanthrane An intimate mixture of parts of l,4a-dimethyl-1- hydroxymethyl 6 methoxy-l,2,3,4,4a,9,10,10a octahydrophenanthrene (O-methylpodocarpinol) and 28.5 parts of boric acid is heated in a reaction vessel for 4 hours at about 'l50-160 C., with occasional agitation during the first hour. While the mixture is maintained at this temperature, it is subjected to a vacuum in order to remove remaining traces of water as a distillate. The mixture is then distilled at a pressure of about 0.1-0.5 mm. in order to decompose the boric acid ester initially formed. The distillation is continued until only a dry white solid remains in the distillation vessel. The distillate collected in this manner is redistilled at about 0.1- 0.5 mm. in order to yield the dehydrated O-methylpodocarpinol which is then converted to 4a-methyl-6-methoxy- 1,2,3,4,4a,9,10,10a-octahydro-l-phenanthrone by ozoniza- 'tion according to the methods described in U. S. 2,764,616. Analogous alkoxy and aralkoxy ethers are obtained by the substitution of equivalent amounts of the corresponding ethers of podocarpinol in the foregoing procedure.

3 EXAMPLE 2 A solution of 27 parts of 4a-methyl-fi bethoxy-1 2,3 4,4a,9,10,10a,-octahydro-l-phenanthrone' .and 15 parts of freshly distilled benzaldehyde in 160 parts of absolute ethanol is mixed with a solution of parts of sodium in 79 parts of absolute ethanol at C. After standing for 7 days at room temperaturein a closed vessel.the reddish-brown reaction mixture is diluted with etherand then poured into a large volumeof water. The organic layer is separated 'and the aqueous'laye-r is extracted with ether. The combined organic solutions are washed. with 10% aqueous sodium. hydroxide and: then-with waterto neutrality. Afterdrying over anhydrous calciumsulfate and filtering,'the solvents are stripped from the filtrate under vacuum: A dark red-residue remains whieh is distilled in' a short-path distillation apparatus. The -2- benzylidenet a-methyl-fi-methoxy-l,2,3',44a;9,10,10a-- oetahydro-l-phenanthrone is collected at about 190-200? C. and 0.08 mm. pressure. 'The' ultraviolet absorption spectrum shows'a maximum at about. 290 millimicrons with a molecular extinction coefiicient of 18,600. The infrared absorption spectrum shows. strong and distinct absorption bands at about 5.98, 6.24, 670,693, 7.27, 7.75, 8.05 and 9.57 microns. The compound has the structural formula EXAMPLE 3 A solution of 5 parts of Z-benzylidene4a methyl-6- methoxy-1,2,3,4,4a-9,l0,IDa-octahydro-l-phenanthrone in parts ofethanol is treated with a solution of 4 parts f 2. t phe y hydraziae:30 p r s of n en ra e sulfuric acid, 30 parts ofi'wa i f'and 80 parts of ethanol. The p cip tat s ollected on a, like; an ec y a ize es oma squsethan. o yield the an e-2.4. p ylhydra one of 2-'bsn yli e-.4a:methyl-. methoxy-l,2,3,4,4a,9;10,IOactahydro l phenanthrone melting at about iii-123C.

EXAMPLE 4: 2-(p-methylbenzylidegze) 4mmethyL6shydr0xy-L2; 3,4,4a,9,10,10a bctzzhydrO-i-phenanthrone A i ima e m xtu e o 3.1mm, ot 4e-mq hy1-6- ethcity-1,2,3,4;4a,9,l0,l0a octahydfo" phena'nthrone; an

" ea e at distillation parts of pyridine hydrochlorideis, flask until sufiici'ent distillate has bejerirernoved 'tol'cause the distillation temperature to rise to dbo'ut210-2l5 (3. The remaining mixture-is then heatedunder reflux for 20 minutes, followingjWhich-it is; poured, with stirring, into 300 parts of hot water. The mixture is allowedto cool for complete separationof'product. 'Ijhe solidprodnet is then collected on"afiltei fand'air driedfor usein the following operation. Thiscomp'ou'ndis :ta-methylehydroxyl-1,2,3,4;4a;9,l0;l0a octahydro 1 phenantli rone It exhibits infrared absorption maxima at.'about 3'.08, 5.92, 6.19, 6.33 and 6.68microns.

A cooled solutionof 25.5 parts of this product1andl7 partsof p-tolualdehyde in 175 partsof absoluteethanol is mixed with a cooled solution 0E5 parts or sodiuirnl in 80 parts of absolute methanol. 'Afte'r 's't orage' un c l}; 1 an hydrous conditions for 3 days the mixture is diluted with ...ether and then poured into a large volume of water containing sufiicient acid to neutralize the alkali present. The organic layer is separated and the aqueous layer exhaustively extracted with ether. The combined organic layers are washed with dilute sodium bicrabonate and then with water to neutrality, dried over anhydrous calcium sulfate, filtered and evaporated. The dark reddish residue is distilled under a pressure of about 0.05 mm. The Z-(p-methylbenzylidene)-4a-methyl-6-hydroxyl',2,3,4,'4a,9,10,lQa-octahydro-l-phenanthrone shows an ultraviolet absorption maximum at about 293 millimicrons with a molecular extinction coefficient of 18,700. Well defined infrared. maxirna are observed at about 6.0, 6.26, 6.72, 6.90, and 7.24 microns. The compound has the structural formula OH OH:

EXAMPLE 5 2- (0,p-dimethylbenzylidene -4a-methyl-6-hydroxy- 1,2,3,4,4a,9,10,1 Oa-octnhydro-I -phenan throne A cooled solution of 51 parts of 4a-methyl-6-hydroxyl,2,3,4,4a,9,10,10a-octahydro 1 phenanthrone and 38 parts of o,p-dimethylbenzaldehyde in 500 parts of anhydrous propanol is mixed with a cooled solution of 10 parts of sodium in parts of absolute ethanol and permitted to stand at room temperature under anhydrous conditions for 5 days. The reaction mixture is then diluted with ether and poured into a large volume of water containing sufficient acid to neutralize the alkali present. The organic layer is separated. The inorganic layer is extracted with ether and the combined organic solutions are washed with dilute sodium bicarbonate and then with water to neutrality. After drying over anhydrous sodium sulfate and filtration, the filtrate is concentrated in vacuo. The residual oil is distilled atabout 0.050.07 mm. pressure to yield the 2-.(o,p-dimethylbenzylidene)-4a-methyl- 6 :hydrox-y 1,2,3,4.4a,9,10,10a-octahydro-l-phenanthrone which shows infrared maxima at about 2.99, 5.99, 6.24, 6.69, 6.89, and 7.25 microns. The compound has the un atura i uaula GHQQHL;

EXAMPLE 6 2 (a naphthylmethylene) 4a methyl 6 methaxy- 1,2,3,4,4a,9,10,10a-octahydro-I-phenanthrone A chilled solution of 54 parts of 4a-methyl-6-methoxy- 1,2,3,4,4a,9,10,l0a octahydro 1 phenanthrone and 45 parts of a-naphthaldehyde in 500 parts of absolute ethanol is treated with a chilled solution of 10 parts of sodium and 160 parts of absolute ethanol and stored under anhydrous conditions for 10 days. The reaction mixture is diluted with ether and poured into a large quantity of water. The organic layer is separated and the aqueous layer is exhaustively extracted with ether. The combined organic solutions are washed with dilute sodium hydroxide and I 5 then with water to neutralit After drying over anhydrous calcium sulfate and filtration the solvents are removed under vacuum to yield 2 (a-naphthylmethylene)- 4a methyl 6 methoxy 1,2,3,4,4a,9,10,10a-octahydrol-phenanthrone which shows prominent infrared maxima at about 6.01, 6.88, 7.23, 8.00, and 9.60 microns. The compound has the structural formula OCH: OH:

EXAMPLE 7 2 (o-fluorobenzylidene) 4a methyl 6 hydrxy-1,2,- 3,4,4a,9,10,10a-0ctahydr0-1-phenanthrone A cooled solution of 51 parts of 4a-methyl-6-hydroxyl,2,3,4,4a,9,10,l0a octahydro 1 phenanthrone and 59 parts of o-fluorobeuzaldehyde in 350 parts of absolute ethanol is mixed with a cold solution of 10 parts of sodium in 160 parts of absolute ethanol. The reaction mixture is maintained at room temperature in a closed vessel for five days, diluted with ether and then poured into a large quantity of water containing suflicient acid to neutralize the alkali present. The organic layer is separated and the aqueous layer is extracted with ether. The combined organic solutions are washed with aqueous sodium bicarbonate and then with water to neutrality. The washed solution is then dried over anhydrous calcium sulfate, filtered and freed from solvent by vacuum distillation to yield the 2 (o fluorobenzylidene) 4a methyl 6 hydroxy l,2,3,4,4a,9,10,10a-octahydro 1 phenanthrone which is distilled at about 0.06-0.08 mm. pressure. The infrared absorption spectrum shows maxima at 3.0, 6.01, 6.24, 6.69, 6.91, and 7.26 microns. The compound has the structural formula EXAMPLE 8 2 (p 7 iodobenzylidene) 4a methyl 6 ethoxy 1,2,- 3,4,4a,9,10,1 0a-0ctahydr0-1 -phenanthrone Under cooling and anhydrous conditions a solution of 58 parts of 4a-methyl-6-ethoxy-1,2,3,4,4a,9,10,10a-octahydro-l-phenanthrone and 66.5 parts of p-iodobenzaldehyde in 500 parts of absolute ethanol is mixed with a solution of 10 parts of sodium in 160 parts of absolute ethanol. After storing under anhydrous conditions for 10 days the reaction mixture is diluted with ether and poured into water. The organic layer is separated and the aqueous layer is extracted with ether. The combined organic layers are washed with dilute ammonium hydroxide and then with water to neutrality, dried over anhydrous calcium sulfate, filtered and evaporated in vacuo. The residual 2 (p iodobenzylidene) 4a methyl 6 ethoxy- 1,2,3,4,4a,9,l0,10a octahydro 1 phenanthrone shows infrared maxima at about 6.02, 6.90, 7.25, 8.00, and 9.60 microns. It has the structural formula o cum CHa l EXAMPLE 9 2 benzylidene 4a methyl 6 benzyloxy 1,2,3,4, 4a,- 9,10,10a-octahydro-I-phenanthrone A solution of 500 parts of 4a-methyl-6-benzyloxy-1,2, 3,4,4a,9,10,10a-octahydro-l-phenanthrone and 222 parts of freshly distilled benzaldehyde in 2500 parts of absolute ethanol is mixed with a solution of 74 parts of sodium in 1200 parts of absolute ethanol at 18 C. After standing at that temperature under anhydrous conditions for 8 days, the reaction mixture is diluted with ether and poured into a large volume of Water. The organic layer is separated and the aqueous layer is extracted with ether. The

combined organic solutions are washed with 10% aqueoussodium hydroxide and then with water to neutrality, dried over anhydrous sodium sulfate, filtered and freed from solvent by vacuum distillation. The residual viscous product shows infrared absorption maxima at about 6.00, 6.26, 6.38, 6.70, and 6.87 microns. The 2-benzylidene- 4a methyl 6 benzyloxy-l,2,3,4,4a,9,10,lOa-octahydrol-phenanthrone has the structural formula OCH C 2 EXAMPLE l0 2 (3,4 dichlorobenzylidene) 4a methyl 6 meth- 0xy-1,2,3,4,4.a,9,10,10a-octahydro-1-phenanthrone T precipitating it, such as by cooling a saturated solution in hot, aqueous methanol. For further purification, it is distilled in a short-path distillation apparatus. At a pressure of about 0.08 mm., a distillate of the desired product is obtained over a distillation range beginning at about 220 C. Upon cooling, the distillate forms a yellow, glassy material. This compound is 2-(3,4-dichlorobenzylidene) 4a methyl 6 methoxy 1,2,3,4, 4a,9,10,l0a-octahydro-l-phenanthrone. It has an ultraviolet absorption maximum at 287 millimicrons with a molecular extinction coefiicient of about 18,400. The

8 specific rotation determined in ethanol solution, is about wherein Ar is an aromatic hydrocarbon radical havin +695 T-hestructural formula is fewer than eleven carbon atoms.

m :3. 2 benzylidene 4a methyl 6 (lowerbalkoxy- CH3 l l,2,3,4,,4a,9,l0,l0a-octahydro l-phenanthrone.

5 4. 2 benzylidene 4ar-methyl 6--. methox y 1,2,3, 4,4a,9,l0;lQa-octahydro-l-phenanthrone.

5.. A compound. of the structural formula 0H OH: l 01 'CH= 10 01 ii -By-' the'foregoing procedure with the substitution of 22 parts o'f Q-chloro-l-naphthaldehyde for the 3,4-dichloro-. bcnzaldehyde, the compound obtained is 2-(2 chloro-1- naphfllylmethylene) 4a methyl .6 methoxy 1,2,3,4, 4a,9,10,10a-octahydro-l-phenanthrone.

What is claimed is: wherein Ar is an aromatic hydrocarbon radical having 1. A compound of the structural formula fewer than eleven carbon atoms.

OR 6. A compound of the rstructuralformula CH3 k CH3 (l) (ower)al yl At-CH- H Ar"GH 0 wherein R is a member of the class consisting of hydro- 0 gen and hydrocarbon radicals having fewer than nine wherein Ar is-an aromatic halohydrocarbon radical havcarbon atoms, and Ar is a member of the class consisting ing fewer than elevencarbon atoms. of aromatic hydrocarbon radicals and aromatic halohy- 7. Acompound of thenstructural formula drocarbon radicals having fewer than eleven carbon 3 0H atoms. 7 CE: I

-2. A compound of the structural formula H O-(lower)alky1 Ar-CH wherein Ar" 15 an aromatic halohydrocarbon radical g having fewer than eleven carbon atoms.

No references cited. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 